CN110402156B

CN110402156B - Methods, systems, and computer readable media for controlling insulin delivery

Info

Publication number: CN110402156B
Application number: CN201880017688.0A
Authority: CN
Inventors: 史蒂芬·D·帕特克; 马克·D·布雷顿
Original assignee: University of Virginia Patent Foundation
Current assignee: University of Virginia Patent Foundation
Priority date: 2017-02-03
Filing date: 2018-02-05
Publication date: 2022-05-03
Anticipated expiration: 2038-02-05
Also published as: AU2018215533A1; EP3576815A4; JP2023100840A; AU2023204573A1; US11179517B2; CN114796704A; US20220040407A1; US20200016336A1; CA3052457C; JP2020507166A; CN110402156A; EP3576815A1; CA3052457A1; CN114796704B; AU2018215533B2; JP7278216B2; WO2018144992A1

Abstract

A retrospective virtual basal rate for an equivalent insulin pump for daily injections is constructed from a database of planned insulin injections, as well as historical insulin injections (i.e., basal injections actually administered by the patient), which are in accordance with a virtual basal rate curve developed for the patient, thereby providing a unified framework for analyzing, designing, optimizing, and modifying MDI (multiple daily insulin injections) and CSII (continuous subcutaneous insulin infusion (i.e., insulin pump)) treatment parameters for diabetic patients.

Description

Methods, systems, and computer readable media for controlling insulin delivery

Cross reference to related applications and priority claims

This application claims benefit of U.S. provisional application serial No. 62/454,282 filed on 2017, 2, 3, 35 u.s.c.119(e) and PCT article 8.

Background

In terms of health, Blood Glucose (BG) is tightly controlled by a hormone network, including the gut, liver, pancreas and brain, to ensure stable fasting BG levels (about 80 to 100mg/dl) and transient postprandial glucose excursions. Diabetes is a combination of conditions characterized by a lack of or impaired insulin action leading to hyperglycemia. Intensive insulin and oral drug therapy to maintain near normal blood glucose levels significantly reduces the chronic complications of type 1 and type 2 diabetes, but may lead to the risk of Severe Hypoglycemia (SH) that can be life threatening. This SH is caused by incomplete insulin replacement, which may reduce warning symptoms and hormonal defense.

Prior to the 70's of the 20 th century, intensive therapy was defined primarily by Multiple Daily Injections (MDI) of insulin, where the time and dosage of each injection was selected to meet the insulin needs throughout the day. For many years, MDI therapy has evolved to include both the use of long acting insulin (e.g., insulin glargine and insulin detemir) (administered once or twice daily) to meet the insulin needs between meals and the use of fast acting insulin (e.g., insulin lispro and insulin aspart) to cover the insulin needs associated with meals. Many patients find insulin pens to be a convenient mechanism for manually injecting insulin.

An insulin pen consists of a vial of insulin (long acting or fast acting insulin), a hypodermic needle and a plunger mechanism integrated into a single pen-like form factor, allowing the patient to "dial in" the required dose. In the 70's of the 20 th century, continuous subcutaneous insulin infusion (CSII, also known as insulin pump) therapy became a viable alternative to MDI. Although CSII treatment is associated with lower glycated hemoglobin (HbA1c), lower glycemic variability, and lower incidence of hypoglycemia, many patients still opt for MDI, in part because of the higher cost associated with insulin pumps and the need for trained supervision of insulin pump use.

BG sensing technology has also undergone similar transitions over the years. Self blood glucose monitoring (SMBG) was emerging in the 60's of the 20 th century, involving the use of lancets and chemical test strips for each sample, replacing the relatively crude and unspecific BG urine analysis method. SMBG is still by far the primary mechanism used to evaluate BG for treatment, usually to correct meal-time insulin doses based on BG levels that are out of range. Continuous Glucose Monitoring (CGM), which takes BG samples every 5 minutes or less, has been available to patients as an adjunct to SMBG over the past decade, allowing patients to more fully understand the blood glucose variability throughout the day. The introduction of CGM has led many groups to devote to the development of safe and effective "artificial pancreas", in which CGM informs CSII of the closed-loop regulation of insulin delivery in real time.

While many patients will benefit from the reduced control burden presented by artificial pancreas, such devices can be expensive and would be primarily appealing to technically-conscious patients. Furthermore, many patients may prefer to maintain control themselves, only wishing to obtain CGM notification recommendations for insulin injections rather than automation.

Systems for providing real-time recommendations to insulin pump users have been studied in "Correction insulin administration system based on medical assisted profiles" by Patek et al, IFAC 18 th world congress, 2011, pages 8354 to 8359, the focus of which is on making optimal meal Correction bolus recommendations as needed, which is incorporated herein by reference.

Also incorporated herein by reference is "mealtitime Correction in Advisor for CGM-lnformed in Pen Therapy" by vereshchelin et al, american control meeting (ACC) meeting record, 6 months 2013, which first discusses the timing of providing CGM notification advice to MDI patients at mealtimes. Specifically, as shown in fig. 12, a "smart" insulin pen 1201 may provide real-time recommendations to the user regarding correction of meal time fast acting insulin/insulin glargine bolus 1202 based on (in addition to SMBG readings) CGM readings received by the wireless blood glucose meter 1203 from a subcutaneously implanted CGM sensor 1204 and (ii) an internal representation of the pharmacokinetic properties of the long acting insulin. Vereshchelin et al attempts to determine the extent to which MDI patients could benefit from algorithmic support for calculating an optimal correction bolus in order to make it possible to develop an integrated insulin pen/CGM receiver for an intelligent insulin pen platform.

Vereshchelin et al propose a nominal model of the Pharmacokinetic (PK) profile of once-daily long-acting insulin, which is incorporated into a computer simulation environment for MDI treatment of type 1 diabetes, and introduce the concept of a "virtual basal rate" curve associated with daily long-acting insulin injections based on the pharmacokinetic model in order to estimate the metabolic state of the patient via kalman filtering. Then, Vereshchelin et alThe metabolic state estimate is used to calculate a corrected bolus recommendation for a meal time fast acting bolus in an MDI therapy. The correction recommendations were evaluated for a type 1 population that achieved a mean HbA1c (standard deviation of 0.52) of 7.98% by a computer-simulated self-treatment strategy, even at the absorption parameter k_d0In the case of a +/-25% variation, the algorithm can also result in a saturation reduction of more than 1% and does not significantly increase the risk of hypoglycemia. The results of computer simulations indicate that the combination of CGM and MDI can be very effective in improving glycemic control in type 1 diabetic patients, achieving many of the benefits of a fully closed-loop pump directed system (e.g., artificial pancreas).

To obtain in silico results, a coarse model of self-treatment was constructed for a population of type 1 subjects in which each model patient was assigned (i) a daily long-acting insulin dose and (ii) a carbohydrate ratio and a correction factor such that the full group achieved a mean HbA1c of 7.98%. The reference treatment model was then adjusted to achieve a reduction in HbA1c, with the risk of hypoglycemia as a secondary criterion.

At mealtimes, the patient may calculate a bolus related to carbohydrate by applying his or her Carbohydrate Ratio (CR) to the estimate of meal size. However, instead of using his/her correction factor, it is done by minimizing the objective function

To calculate an insulin correction that adjusts the current state of the patient (e.g., high or low BG at meal time).

Where K is the phase at which the patient intends to deliver a meal time bolus of rapid acting insulin, N is the scheduled interval (e.g., N-72 five minute intervals, i.e., 6 hours), Q and R are the semi-positive and explicit weighting matrices, respectively, Δ is the BG offset required, and

under the following control:

the correction insulin bolus u is applied only at phase K in the above equation and the only other change in insulin is due to the Pharmacokinetic (PK) characteristics of the long-acting insulin injected at K ═ 0. Taking x (kappa) as a Kalman Filter estimate of the patient State

As shown in FIG. 13, the meal time correction bolus algorithm is designed as follows. It is assumed that the patient is interested in recommendations regarding an optimal correction bolus at discrete time K. The first step of the algorithm is based on CGM/SMBG measurements and a virtual basic deviation u of the patient up to K^LARate to calculate an estimate of the metabolic state of the patient

CGM and algorithm parameters input into Kalman filter

In connection therewith, the algorithm parameters may be initialized based on the patient's daily average blood glucose concentration and then adjusted as the patient achieves a better glycemic outcome. In practice, the meal time SMBG samples will be used in calculating the estimated results

The CGM history was previously adjusted (to eliminate the effect of sensor drift). The next step of the algorithm is based on (i) the current estimate of the patient's metabolic state and (ii) a virtual basal rate signal u^LA(ii) and (iii) the desired offset Δ to calculate an LQ (linear quadratic) optimal discrete correction bolus. The offset Δ allows the patient to compensate for a poorly titrated long acting insulin dose, so that if the long acting dose is too low (resulting in a high average BG), the correction bolus can be designed to achieve a BG offset that is applicable for at least the action duration of the correction bolus. The parameters q and Δ may be considered as tuning parameters of the algorithm.

Disclosure of Invention

According to an aspect of the present invention, a method, system and computer readable medium are provided for constructing an equivalent insulin pump retrospective virtual basal rate from a database of planned insulin injections, as well as historical insulin injections (i.e., basal injections actually administered by the patient), that conform to a virtual basal rate curve developed for the patient, thereby providing a unified framework for analyzing, designing, optimizing and modifying MDI (multiple daily insulin injections) and CSII (continuous subcutaneous insulin infusion (i.e., insulin pump)) treatment parameters for diabetic patients.

Another aspect of the present invention provides a method, system and computer readable medium for virtualizing retrospective virtual basal rates from planned and historical insulin deliveries.

Drawings

FIG. 1 is a block diagram of a virtual basal rate system in accordance with an aspect of the subject invention;

FIG. 2 is a graph of a virtual basal rate curve for a planned daily insulin injection over 24 hours;

FIG. 3 is a graph of a retrospective (historical) virtual basal rate from an actual recording of insulin injections and a virtual basal rate curve from a planned injection, showing the variation between them due to actual patient behavior;

FIG. 4 is a table of user recorded insulin injections history;

FIG. 5 is a block diagram of an example of a machine on which one or more aspects of embodiments of the present invention may be implemented;

FIG. 6A is a block diagram of a computing device on which one or more aspects of embodiments of the present invention may be implemented;

FIG. 6B illustrates a network system upon which one or more aspects of embodiments of the invention may be implemented;

FIG. 7 illustrates a system in which one or more embodiments of the invention may be implemented using a computer network or portions thereof;

FIG. 8 illustrates a system in which one or more embodiments of the invention may be implemented using a computer network or portions thereof;

FIG. 9 illustrates a block diagram of an example machine 400 upon which one or more embodiments of the invention may be implemented;

FIGS. 10 and 11 are schematic diagrams of a wireless blood glucose meter for use with embodiments of the present invention;

FIG. 12 is a block diagram of a prior art generic intelligent insulin pen system that may be used with the present invention; and

FIG. 13 is a block diagram of a prior art meal time correction bolus algorithm that may be used in conjunction with the present invention.

Detailed Description

According to an embodiment of the present invention, Pharmacokinetic (PK) characteristics of insulin, in particular intermediate and long acting insulin products, are used to construct a planned CSII virtual basal rate curve, and actual history of insulin injections by the patient are used to construct a retrospective virtual basal rate. Insulin units injected or administered to the patient according to the planned injection according to the virtual basal rate curve are then modified according to the retrospective virtual basal rate to provide the patient with a more accurate dosage based on the patient's actual insulin administration history.

Virtual base rate curve

Based on a consistent daily injection pattern (including where injections are made multiple times at different times of the day), the system (and related systems) performs the following operations:

use of the PK profile of insulin to infer a finite persistence pattern of plasma insulin concentrations over a 24-hour cycle, and then

Using the PK profile of rapid-acting insulin delivered by CSII to determine a sustained CSII basal rate profile that would achieve the same pattern of plasma insulin concentrations over a 24-hour cycle.

Fig. 2 shows a virtual basal rate curve 201, which is calculated according to the planned daily interval in the morning of 06: 00 injections of 19.6 units of insulin glargine. The y-axis of the graph has units of U/hour. Note that the time average of the virtual basal rate curve is.8167U/hr (dashed line), matching 19.6 units of insulin scheduled for 24 hours a day. The change in the virtual basal rate curve around this mean is due to the PK profile of insulin glargine, which (although a popular conceptual view) is not flat over a 24 hour period, but describes the rise time and decay from the peak concentration that is measurable throughout the day.

Referring to fig. 1, a virtual base rate curve 101 may be constructed as follows:

1. given an insulin injection plan 102, the subsystem 103 uses a mathematical model of the PK properties of insulin to infer a steady state trajectory for plasma insulin concentration, assuming that the plan has been accurately followed in the past at infinity:

tau is at [0, T_day]Within the range of (A) and (B),

wherein, I_steadystate(τ) the planned infusion expressed based on the function J (σ) describing the plasma insulin concentration at the time τ over 24 hours a day, the function J (σ) describing the interval [0, T_day]The injection intended is shown at each time σ within 24 hours of the day. Here, F_steadystateIs a function describing the steady state plasma concentration derived from the planned daily injection and the specific PK parameter θ of the insulin type under consideration.

2. Using the PK characteristics of rapid-acting insulin delivered via the CSII insulin pump, the subsystem 103 infers a virtual basal rate curve

Which describes a basal infusion mode, a corresponding steady-state mode of plasma insulin concentration in this mode

Matched to the plasma insulin concentration pattern from daily injections, i.e.:

all tau are at [0, T_day]Within the range.

Trace 301 in FIG. 3 shows, as an example, the historical virtual basal rate derived from actual insulin glargine injection recordings over a time period of 9/21/15 to 10/2/15 as shown in FIG. 4. In fig. 3, trace 302 shows the average of the measured values at 06: 00 projected injection of 19.6 units of insulin. As can be seen in fig. 4, the patient missed the long-acting insulin injection on days 23, 25, 26 and 30. These missed insulin injections result in significant basal rate deviations from the virtual basal rate curve obtained according to the plan. The present invention provides a new method of quantifying the effects of inaccurate insulin delivery as opposed to a planned injection based on a curve obtained by the patient.

Retrospective virtual base rate

Referring back to fig. 1, based on the history of insulin injections 104 (including timing and dose amounts and allowing for the possibility of missed injections over multiple days), the subsystem 105 constructs a retrospective virtual basal rate 106 by:

using the PK characteristics of insulin to infer the plasma insulin concentration over time resulting from an injection, and then

Using the PK profile of rapid acting insulin delivered by CSII to determine a sustained CSII basal rate profile that will achieve the same historical concentration of plasma insulin concentrations over a 24 hour cycle.

A virtual basal rate curve may be constructed as follows:

1. given the actual insulin injection record over a given period of time,

sigma at [0, T]Within the range of (A) and (B),

where T is the length of the time period (usually corresponding to multiple days), the system uses a mathematical model of the PK profile of insulin to infer the plasma insulin concentrations resulting from those injections:

tau is at [0, T]Within the range of (A) and (B),

wherein, I_transient(τ) represents the plasma insulin concentration at time τ in the history. Here, F_transientIs a function describing the specific (instantaneous) plasma concentration from historical injections given (I) the specific PK parameter θ for the insulin type under consideration and (ii) the given initial plasma insulin concentration I (0) (if the initial plasma insulin concentration is not known, the initial plasma insulin concentration can be estimated from the steady state values obtained in the above-described virtual basal rate curve calculation).

2. Using PK characteristics of rapid-acting insulin delivered by CSII insulin pump, the system infers a virtual history of basal rate insulin delivery

Corresponding to the instantaneous plasma insulin concentration

Matched to the plasma insulin concentration pattern from historical injections, i.e.:

all τ are in the [0, T ] range.

Fig. 10 shows an example of how a user may enter and confirm an insulin injection according to the user's basal rate profile. The user enters the insulin unit to be injected in an input area 1001 on the display of the wireless glucose meter 1204 and may approve the amount or cancel the injection by using the "cancel" and "approve" touch sensitive buttons 1002. The glucose meter 1203 then displays a screen as shown in fig. 11, requesting the user to confirm that the indicated insulin dose was injected using the touch sensitive button 1101. After confirmation, the date and time are recorded in the database 104 along with the injected insulin units.

One aspect of the present invention may provide many novel and nonobvious features, elements, and characteristics, as well as advantages, as discussed below. For example, one advantage of the basic virtualization is that it allows applying retrospective methods (e.g., therapy optimization) and online methods (e.g., real-time assessment and control of diabetes) originally developed for insulin pump users to a large population of diabetic patients for Multiple Daily Injection (MDI) therapy.

An aspect of various embodiments of the present invention may be used for many products and services, such as but not limited to products and services as discussed below. The base virtualization can be used for any retrospective or real-time application of insulin delivery, typically by CSII (insulin pump). An aspect of one embodiment of the invention provides for base virtualization: (i) use in therapy optimization, wherein basal insulin requirements are achieved by daily manual injection of long acting insulin; and (ii) use in a system for real-time treatment recommendation (e.g. bolus or exercise recommendation), wherein the basal virtualization helps to optimally estimate the metabolic state of the patient. The retrospective application described above will naturally fit into a "cloud" analysis framework, while real-time applications may take the form of a mix of "cloud" and embedded computing.

An aspect of an embodiment of the present invention may be used for, but is not limited to, various "cloud analysis" applications in the treatment of diabetes (type 1 and type 2).

Fig. 5 is a high-level functional block diagram of an embodiment of the invention, or an aspect of an embodiment of the invention, shown in fig. 1, where the system shown in fig. 1 may be implemented in a processor or controller 502 of fig. 5.

As shown in fig. 5, a processor or controller 502 is in communication with a glucose monitor or device 501 and an optional insulin device 500. A glucose monitor or device 501 communicates with subject 103 to monitor the glucose level of subject 103. The processor or controller 102 is configured to perform the required calculations. Optionally, insulin device 500 communicates with subject 503 to deliver insulin to subject 503. The processor or controller 502 is configured to perform the required calculations. The glucose monitor 501 and the insulin device 500 may be implemented as separate devices or as a single device. The processor 502 may be implemented locally in the glucose monitor 501, the insulin device 500, or a stand-alone device (or in any combination of two or more of the glucose monitor, the insulin device, or the stand-alone device). The processor 502 or a portion of the system may be remotely located such that the device operates as a telemedicine device.

Referring to fig. 6A, in its most basic configuration, computing device 144 (e.g., processor 502 shown in fig. 5) typically includes at least one processing unit 150 and memory 146. Depending on the exact configuration and type of computing device, memory 146 may be volatile (such as RAM), non-volatile (such as ROM, flash memory, etc.) or some combination of the two.

Additionally, device 144 may also have other features and/or functionality. For example, the device may also include additional removable and/or non-removable storage including, but not limited to, magnetic or optical disks or tape, and writable electrical storage media. Such additional storage is a graphic of removable storage 152 and non-removable storage 148. Computer storage media includes volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data. Memory, removable storage and non-removable storage are all examples of computer storage media. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology CDROM, Digital Versatile Disks (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by the device. Any such computer storage media may be part of, or used in conjunction with, the apparatus.

The device may also contain one or more communication connections 154 that allow the device to communicate with other devices, such as other computing devices. The communication connection carries information in a communication medium. Communication media typically embodies computer readable instructions, data structures, program modules or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term "modulated data signal" means a signal that has one or more of its characteristics set or changed in such a manner as to encode, execute, or process information in the signal. By way of example, and not limitation, communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as radio, RF, infrared and other wireless media. As described above, the term computer readable media as used herein includes both storage media and communication media.

In addition to stand-alone computing machines, embodiments of the invention may also be implemented on a network system comprising a plurality of computing devices in communication with a networking apparatus (e.g., a network with infrastructure or an ad hoc network). The network connection may be a wired connection or a wireless connection. By way of example, FIG. 6B illustrates a network system in which embodiments of the invention may be implemented. In this example, the network system includes a computer 156 (e.g., a web server), a network connectivity device 158 (e.g., a wired and/or wireless connection), a computer terminal 160, and a PDA (e.g., a smart phone) 162 (or other handheld or portable device such as a cell phone, laptop, tablet, GPS receiver, mp3 player, handheld video player, pocket projector, etc., or a handheld device (or non-portable device) having a combination of these features). In an embodiment, it should be appreciated that the modules listed as 156 may be glucose monitoring devices. In an embodiment, it should be appreciated that the modules listed as 156 may be glucose monitoring devices (or glucose meters) and/or insulin devices. The number of any components shown or discussed in fig. 6B may be multiple. Embodiments of the invention may be implemented in any device of a system. For example, execution of instructions or other desired processing may be performed on the same computing device as any of 156, 160, and 162. Alternatively, embodiments of the present invention may be implemented on different computing devices of a network system. For example, some desired or required processing or execution may occur at one of the computing devices of the network (e.g., server 156 and/or glucose monitoring device), while execution of other processing and instructions may occur at another computing device of the network system (e.g., terminal 160), or vice versa. Indeed, some processing or execution may occur at one computing device (e.g., server 156 and/or glucose monitoring device); and execution of other processes or instructions may occur at different computing devices that may or may not be networked. For example, some processing may be performed at terminal 160 while other processing or instructions are passed to device 162, with the instructions being executed at device 162. This may be particularly valuable, particularly when the PDA162 device accesses the network, for example, via the computer terminal 160 (or access point in an ad hoc network). Also for example, software to be protected may be executed, encoded, or otherwise processed with one or more embodiments of the invention. The processed, encoded, or executed software may then be distributed to customers. The distribution may be in the form of a storage medium (e.g., a disk) or an electronic copy.

FIG. 7 is a block diagram illustrating a system 130 on which embodiments described herein may be implemented, the system 130 including a computer system 140 and an associated Internet 11 connection. Such a configuration is typically used for a computer (host) that connects to the internet 11 and executes server or client (or combination) software. For example, source computers such as laptops, final destination computers, and relay servers, as well as any computer or processor described herein, may use the computer system configuration and internet connection shown in fig. 7. The system 140 may be used as a portable electronic device such as a notebook/laptop computer, a media player (e.g., an MP 3-based player or a video player), a cellular telephone, a Personal Digital Assistant (PDA), a glucose monitoring device, an insulin delivery device, an image processing device (e.g., a digital camera or video recorder), and/or any other handheld computing device or combination of any of these devices. Note that while fig. 7 illustrates various components of a computer system, it is not intended to represent any particular architecture or manner of interconnecting the components; as such details are not germane to the present invention. It will also be appreciated that network computers, hand-held computers, cellular telephones, and other data processing systems which have fewer components or perhaps more components may also be used. For example, the computer system of FIG. 7 may be an Apple Macintosh computer or Power Book, or an IBM compatible PC. Computer system 140 includes a bus 137, or interconnect or other communication mechanism for communicating information, and a processor 138, typically in the form of an integrated circuit coupled with bus 137 for processing information and executing computer-executable instructions. Computer system 140 also includes a main memory 134, such as a Random Access Memory (RAM) or other dynamic storage device, coupled to bus 137 for storing information and instructions to be executed by processor 138.

Main memory 134 also may be used for storing temporary variables or other intermediate information during execution of instructions to be executed by processor 138. Computer system 140 further includes a read only memory 136(ROM) (or other non-volatile memory) or other static storage device coupled to bus 137 for storing static information and instructions for processor 138. A storage device 135, such as a magnetic or optical disk, a hard disk drive for reading from and writing to a hard disk, a magnetic disk drive for reading from and writing to a magnetic disk, and/or an optical disk drive for reading from or writing to a removable optical disk (e.g., a DVD), is coupled to bus 137 for storing information and instructions. The hard disk drive, magnetic disk drive, and optical disk drive can be connected to the system bus by a hard disk drive interface, a magnetic disk drive interface, and an optical drive interface, respectively. The drives and their associated computer-readable media provide nonvolatile storage of computer-readable instructions, data structures, program modules and other data for the general purpose computing device. Generally, computer system 140 includes an Operating System (OS) stored in non-volatile storage for managing computer resources and provides applications and programs with access to computer resources and interfaces. The operating system typically processes system data and user input and responds by allocating and managing tasks and internal system resources, such as controlling and allocating memory, prioritizing system requests, controlling input and output devices, facilitating networking, and managing files. Non-limiting examples of operating systems are Microsoft Windows, Mac OS X, and Linux.

The term "processor" is intended to include any integrated circuit or other electronic device (or collection of devices) capable of performing an operation on at least one instruction, including, but not limited to, Reduced Instruction Set Core (RISC) processors, CISC microprocessors, microcontroller units (MCUs), CISC-based Central Processing Units (CPUs), and Digital Signal Processors (DSPs). The hardware of these devices may be integrated onto a single substrate (e.g., a silicon "slice"), or distributed between two or more substrates. Furthermore, various functional aspects of the processor may be implemented solely as software or firmware associated with the processor.

Computer system 140 may be coupled via bus 137 to a display 131, such as a Cathode Ray Tube (CRT), Liquid Crystal Display (LCD), flat screen monitor, touch screen monitor or the like for displaying textual and graphical data to a user. The display may be connected via a video adapter for supporting the display. The display allows a user to view, enter, and/or edit information related to the operation of the system. An input device 132, including alphanumeric and other keys, is coupled to bus 137 for communicating information and command selections to processor 138. Another type of user input device is cursor control 133, such as a mouse, a trackball, or cursor direction keys for communicating direction information and command selections to processor 138 and for controlling cursor movement on display 131. The input device typically has two degrees of freedom in two axes, a first axis (e.g., x) and a second axis (e.g., y), which allows the device to specify positions in a plane.

Computer system 140 may be used to implement the methods and techniques described herein. According to one embodiment, those methods and techniques are performed by computer system 140 in response to processor 138 executing one or more sequences of one or more instructions contained in main memory 134. Such instructions may be read into main memory 134 from another computer-readable medium, such as storage device 135. Execution of the sequences of instructions contained in main memory 134 causes processor 138 to perform the process steps described herein. In alternative embodiments, hard-wired circuitry may be used in place of or in combination with software instructions to implement the arrangement. Thus, embodiments of the invention are not limited to any specific combination of hardware circuitry and software.

The term "computer-readable medium" (or "machine-readable medium") as used herein is an extensible term referring to any medium or any memory that participates in providing instructions to a processor (e.g., processor 138) for execution or any mechanism for storing or transmitting information in a form readable by a machine (e.g., a computer). Such a medium may store computer-executable instructions to be executed by a processing element and/or control logic, and data which is manipulated by a processing element and/or control logic, and may take many forms, including but not limited to, non-volatile media, and transmission media. Transmission media include coaxial cables, copper wire and fiber optics, including: including the lines of bus 137. Transmission media can also take the form of acoustic or light waves, such as those generated during radio wave and infrared data communications, or other forms of propagated signals (e.g., carrier waves, infrared signals, digital signals, etc.). Common forms of computer-readable media include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, or any other magnetic medium, a CD-ROM, any other optical medium, punch cards, paper tape, any other physical medium with patterns of holes, a RAM, a PROM, and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave as described hereinafter, or any other medium from which a computer can read.

Various forms of computer readable media may be involved in carrying one or more sequence of one or more instructions to processor 138 for execution. For example, the instructions may initially be carried on a magnetic disk of a remote computer. The remote computer can load the instructions into its dynamic memory and send the instructions over a telephone line using a modem. A modem local to computer system 140 can receive the data on the telephone line and use an infra-red transmitter to convert the data to an infra-red signal. An infra-red detector can receive the data carried in the infra-red signal and appropriate circuitry can place the data on bus 137. Bus 137 delivers data to main memory 134 and processor 138 retrieves and executes instructions from main memory 134. The instructions received by main memory 134 may optionally be stored on storage device 135 either before or after execution by processor 138.

Computer system 140 also includes a communication interface 141 coupled to bus 137. Communication interface 141 provides a two-way data communication coupling to a network link 139 that is connected to local network 111. For example, communication interface 141 may be an Integrated Services Digital Network (ISDN) card or a modem to provide a data communication connection to a corresponding type of telephone line. As another non-limiting example, communication interface 141 may be a Local Area Network (LAN) card to provide a data communication connection to a compatible LAN. For example, an IEEE802.3 standard based Ethernet-based connection may be used, such as 10/100BaseT, 1000BaseT (gigabit Ethernet), 10 gigabit Ethernet (10GE or 10GbE or 10GigE, with IEEE standard 802.3ae-2002 as standard), 40 gigabit Ethernet (40GbE) or 100 gigabit Ethernet (100GbE, according to the Ethernet standard IEEE P802.3ba), such as Sechikuku systems corporation, published under the publication number 1-587005-001-3(6/99) "Chapter Internetwork Technologies Handbook", 7: "Ethernet Technologies" as described on pages 7-1 to 7-38, the entire contents of which are incorporated herein for all purposes as if fully set forth herein. In this case, the communication interface 141 typically includes a LAN transceiver or modem, such as the Standard microsystems corporation (SMSC) data sheet "LAN 91C 11110/100 Non-PCI Ethernet Single Chip MAC + PHY" data sheet, the Standard microsystems corporation (SMSC) LAN91C 11110/100 Ethernet transceiver described in Rev.15(02-20-04), the entire contents of which are incorporated herein for all purposes as if fully set forth herein.

Wireless links may also be implemented. In any such implementation, communication interface 141 sends and receives electrical, electromagnetic or optical signals that carry digital data streams representing various types of information. Network link 139 typically provides data communication through one or more networks to other data devices. For example, network link 139 may provide a connection through local network 111 to a host computer or to data equipment operated by an Internet service provider 142 (ISP). ISP 142 in turn provides data communication services through the global packet data communication network internet 11. Local network 111 and Internet 11 both use electrical, electromagnetic or optical signals that carry digital data streams. The signals through the various networks and the signals on network link 139 and through communication interface 141, which carry the digital data to and from computer system 140, are exemplary forms of carrier waves transporting the information. The received code may be executed by processor 138 as it is received, and/or may be stored in storage device 135 or other non-volatile storage for later execution. In this manner, computer system 140 may obtain application code in the form of a carrier wave.

Concepts of a method and system for virtualizing virtual basal rates from planned and historical insulin delivery have been developed and disclosed herein; and the concepts may be implemented and utilized with associated processors, networks, computer systems, the internet, and components and functions in accordance with the aspects disclosed herein.

FIG. 8 illustrates a system in which one or more embodiments of the invention may be implemented using a network, or a portion of a network or computer, but the glucose appliance of the invention may also be practiced without a network.

Fig. 8 schematically illustrates an exemplary system in which examples of the invention may be implemented. In embodiments, the glucose monitor or glucose meter (and/or insulin pump) may be implemented locally by the subject (or patient) at home or other desired location. However, in alternative embodiments, it may be implemented in a clinical setting or an auxiliary setting. For example, referring to fig. 8, the clinical setting 158 provides a place for a physician (e.g., 164) or clinician/assistant to diagnose a patient (e.g., 159) with a glucose-related disease and related diseases and conditions. The glucose monitoring device 10 may be used as a stand-alone device to monitor and/or test the glucose level of a patient. It should be understood that although only the glucose monitoring device 10 is shown, the system of the present invention and any of its components may be used in the manner shown in FIG. 8. The system or component may be secured to or in communication with the patient as needed or desired. For example, a combination of systems or components thereof, including the glucose monitoring device 10 (or other associated devices or systems (e.g., a controller and/or an insulin pump) or any other desired or required devices or components), may be in contact with, in communication with, or secured to a patient via a belt or tubing (or other medical instrument or component), or may communicate via a wired or wireless connection. Such monitoring and/or testing may be short-term (e.g., clinical visit) or long-term (e.g., clinical hospitalization or home). A physician (clinician or assistant) may use the glucose monitoring device output to perform an appropriate action, such as insulin injection or feeding or other appropriate action or modeling of the patient. Alternatively, the glucose monitoring device output may be delivered to the computer terminal 168 for immediate or future analysis. The transmission may be by cable or wireless or any other suitable medium. Glucose monitoring device output from the patient may also be delivered to a portable device, such as PDA 166. The glucose monitoring device output with improved accuracy may be transmitted to the glucose monitoring center 172 for processing and/or analysis. This delivery may be accomplished in a number of ways, such as a network connection 170, which may be wired or wireless.

In addition to the glucose monitoring device output, the error, parameters for accuracy improvement, and any accuracy-related information may also be conveyed to, for example, computer 168 and/or glucose monitoring center 172 for error analysis. Due to the importance of glucose sensors, this may provide centralized accuracy monitoring, modeling, and/or accuracy enhancement for glucose centers.

Examples of the invention may also be implemented in a stand-alone computing device associated with a target glucose monitoring device. An exemplary computing device (or portions thereof) in which examples of the invention may be implemented is schematically illustrated in FIG. 6A.

FIG. 9 is a block diagram illustrating an example of a machine on which one or more aspects of embodiments of the present invention may be implemented.

Fig. 9 illustrates a block diagram of an example machine 400 on which one or more embodiments (e.g., the discussed methods) may be implemented (e.g., executed).

An example of the machine 400 may include logic, one or more components, circuits (e.g., modules), or mechanisms. A circuit is a tangible entity configured to perform certain operations. In an example, the circuitry may be arranged in a specified manner (e.g., internally or with respect to an external entity such as other circuitry). In an example, one or more computer systems (e.g., a standalone client or server computer system) or one or more hardware processors (processors) may be configured by software (e.g., instructions, application portions, or applications) as circuitry that operates to perform certain operations as described herein. In an example, the software may reside (1) on a non-transitory machine readable medium or (2) in a transmission signal. In an example, software, when executed by underlying hardware of a circuit, causes the circuit to perform certain operations.

In an example, the circuitry may be implemented mechanically or electronically. For example, the circuitry may comprise dedicated circuitry or logic specifically configured to perform one or more of the techniques discussed above, including for example a dedicated processor, a Field Programmable Gate Array (FPGA), or an Application Specific Integrated Circuit (ASIC). In an example, the circuitry may include programmable logic (e.g., circuitry contained within a general-purpose processor or other programmable processor) that may be temporarily configured (e.g., via software) to perform certain operations. It is to be appreciated that decisions to implement a circuit mechanically (e.g., in a dedicated and permanently configured circuit) or in a temporarily configured circuit (e.g., configured by software) can be made by cost and time considerations.

Thus, the term "circuit" is understood to encompass a tangible entity, meaning an entity that is physically constructed, permanently configured (e.g., hardwired), or temporarily (e.g., temporarily) configured (e.g., programmed) to operate in a specified manner or to perform a specified operation. In an example, given a plurality of temporarily configured circuits, each of these circuits need not be configured or instantiated at any one time. For example, where the circuitry includes a general purpose processor configured by software, the general purpose processor may be configured at different times as corresponding different circuitry. Thus, software may configure a processor to, for example, configure one particular circuit at a time and different circuits at different times.

In an example, a circuit may provide information to and receive information from other circuits. In this example, the circuit may be considered to be communicatively coupled to one or more other circuits. Where a plurality of such circuits are present at the same time, communication may be achieved by signal transmission (e.g., through appropriate circuits and buses) connecting the circuits. In embodiments where multiple circuits are configured or instantiated at different times, communication between the circuits may be accomplished, for example, by storing and retrieving information in a memory structure accessible to the multiple circuits. For example, one circuit may perform an operation and store the output of the operation in a memory device communicatively coupled thereto. Another circuit may then access the memory device at a later time to retrieve and process the stored output. In an example, a circuit may be configured to initiate or receive communication with an input or output device and may operate on a resource (e.g., a set of information).

Various operations of the method examples described herein may be performed, at least in part, by one or more processors that are temporarily configured (e.g., by software) or permanently configured to perform the relevant operations. Whether temporarily configured or permanently configured, such processors may constitute processor-implemented circuits that operate to perform one or more operations or functions. In an example, the circuitry referred to herein may comprise processor-implemented circuitry.

Similarly, the methods described herein may be implemented at least in part by a processor. For example, at least some of the operations of a method may be performed by one or more processors or processor-implemented circuits. Execution of certain operations may be distributed among one or more processors, and not merely resident in a single machine, but deployed across multiple machines. In an example, one or more processors may be located at a single location (e.g., within a home environment, an office environment, or as a server farm), while in other examples, processors may be distributed across multiple locations.

The one or more processors may also operate to support execution of related operations in a "cloud computing" environment or to operate as a "software as a service" (SaaS). For example, at least some of the operations may be performed by a set of computers (as an example of machines including processors), where the operations may be accessed via a network (e.g., the internet) and via one or more appropriate interfaces (e.g., Application Program Interfaces (APIs)).

Example embodiments (e.g., an apparatus, system, or method) may be implemented in digital electronic circuitry, computer hardware, firmware, software, or any combination thereof. Example embodiments may be implemented using a computer program product (e.g., a computer program tangibly embodied in an information carrier or in a machine-readable medium for execution by, or to control the operation of, data processing apparatus, such as a programmable processor, a computer, or multiple computers).

A computer program can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a software module, subroutine, or other unit suitable for use in a computing environment. A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and interconnected by a communication network.

In an example, the operations may be performed by one or more programmable processors executing a computer program to perform functions by operating on input data and generating output. Examples of method operations may also be performed by, special purpose logic circuitry, e.g., a Field Programmable Gate Array (FPGA) or an Application Specific Integrated Circuit (ASIC), which may be implemented as special purpose logic circuitry.

The computing system may include clients and servers. The client and server are typically remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. In an embodiment where a programmable computing system is deployed, it is to be understood that both hardware and software architectures need to be considered. In particular, it is to be understood that the choice of whether to implement a particular function in permanently configured hardware (e.g., an ASIC), in temporarily configured hardware (e.g., a combination of software and a programmable processor), or in a combination of permanently and temporarily configured hardware may be a design choice. The following lists hardware (e.g., machine 400) and software architectures that may be deployed in an example embodiment.

In an example, the machine 400 may operate as a standalone device, or the machine 400 may be connected (e.g., networked) to other machines.

In a networked deployment, the machine 400 may operate in the capacity of a server or a client machine in server-client network environment. In an example, the machine 400 may operate in the capacity of a peer-to-peer machine in a peer-to-peer (or other distributed) network environment. The machine 400 may be a Personal Computer (PC), a tablet PC, a set-top box (STB), a Personal Digital Assistant (PDA), a mobile telephone, a network appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken (e.g., performed) by the machine 400. Further, while only a single machine 400 is illustrated, the term "machine" shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein.

An example machine (e.g., computer system) 400 may include a processor 402 (e.g., a Central Processing Unit (CPU), a Graphics Processing Unit (GPU), or both), a main memory 404 and a static memory 406, some or all of which may communicate with each other via a bus 408. The machine 400 may also include a display unit 410, an alphanumeric input device 412 (e.g., a keyboard), and a User Interface (UI) navigation device 411 (e.g., a mouse). In an example, the display unit 410, the input device 412, and the UI navigation device 414 may be a touch screen display. The machine 400 may additionally include a storage device (e.g., drive unit) 416, a signal generation device 418 (e.g., a speaker), a network interface device 420, and one or more sensors 421, such as a Global Positioning System (GPS) sensor, compass, accelerometer, or other sensor.

The storage device 416 may include a machine-readable medium 422 having stored thereon one or more sets of data structures or instructions 424 (e.g., software) embodying or utilized by any one or more of the methodologies or functions described herein. The instructions 424 may also reside, completely or at least partially, within the main memory 404, within static memory 406, or within the processor 402 during execution thereof by the machine 400. In an example, one or any combination of the processors 402, the main memory 404, the static memory 406, or the storage device 416 may constitute machine-readable media.

While the machine-readable medium 422 is shown to be a single medium, the term "machine-readable medium" can include a single medium or multiple media (e.g., a centralized or distributed database, and/or associated caches and servers) configured to store the one or more instructions 424. The term "machine-readable medium" shall also be taken to include any tangible medium that is capable of storing, encoding or carrying instructions for execution by the machine and that cause the machine to perform any one or more of the methodologies of the present disclosure, or that is capable of storing, encoding or carrying data structures utilized by or associated with such instructions. The term "machine-readable medium" shall accordingly be taken to include, but not be limited to, solid-state memories and optical and magnetic media. Specific examples of machine-readable media can include non-volatile memory, including, for example, semiconductor memory devices (e.g., electrically programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM)) and flash memory devices; magnetic disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

The transmission medium may also be used to communicate over a communication network via the network interface device 420 using any of a number of transmission protocols (e.g., frame relay, IP, TCP, UDP, HTTP, and the like)426 sends or receives instructions 424. Example communication networks can include a Local Area Network (LAN), a Wide Area Network (WAN), a packet data network (e.g., the internet), a mobile telephone network (e.g., a cellular network), a Plain Old Telephone (POTS) network, and a wireless data network (e.g., referred to as

Of the IEEE 802.11 family of standards, called

IEEE 802.16 family of standards), peer-to-peer (P2P) networks, and the like. The term "transmission medium" shall be taken to include any intangible medium that is capable of storing, encoding or carrying instructions for execution by the machine and that includes digital or analog communications signals or other intangible medium to facilitate communication of such software.

It should be understood that any of the components or modules referred to with respect to any of the embodiments of the invention discussed herein may be formed integrally with one another or separately. In addition, redundant functions or structures of components or modules may be implemented. Further, the various components may communicate locally and/or remotely with any user/clinician/patient or machine/system/computer/processor. Further, the various components may communicate via wireless and/or hardwired or other desired and available communication devices, systems and hardware. In addition, various components and modules may be replaced with other modules or components that provide similar functionality.

It should be understood that the devices and related components discussed herein may take on all shapes along the entire continuous range of geometric manipulation of the x, y and z planes to provide and meet anatomical, environmental and structural requirements and operational requirements. In addition, the location and alignment of the various components may vary as needed or desired.

It should be appreciated that the various sizes, dimensions, profiles, stiffnesses, shapes, compliances, and materials of any component or portion of a component in the various embodiments discussed throughout this document may be varied and utilized as needed or desired.

It will be appreciated that although some dimensions are provided in the foregoing figures, the apparatus may be constructed of various sizes, dimensions, profiles, stiffnesses, shapes, compliances and materials suitable for the components or parts of the components of the apparatus and may therefore be varied and utilized as required or desired.

In sum, while the invention has been described with respect to specific embodiments, many modifications, variations, changes, substitutions, and equivalents will be apparent to those skilled in the art. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Accordingly, the invention should be considered as limited only by the spirit and scope of the disclosure, including all modifications and equivalents.

Other embodiments will become readily apparent to those skilled in the art from a reading of the above detailed description of the specific exemplary embodiments and the accompanying drawings. It should be understood that numerous variations, modifications, and other embodiments are possible, and accordingly, all such variations, modifications, and embodiments are to be regarded as being within the spirit and scope of this application. For example, regardless of the content of any portion of this application (e.g., title, technical field, background, summary, abstract, drawing figure, etc.), there is no requirement that any specifically described or illustrated activity or element, any particular order of such activities, or any particular interrelationship of such elements, be included in any claim of any application herein or that priority be claimed, unless explicitly stated to the contrary. Further, any activity may be repeated, any activity may be performed by multiple entities, and/or any element may be replicated. Further, any activity or element can be excluded, the order of activity can vary, and/or the interrelationship of elements can vary. No particular description or illustration of any activity or element, any particular order of such activities, any particular size, speed, material, size or frequency of such elements, or any particular interrelationship is required unless explicitly stated to the contrary. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. Further, when any number or range is described herein, the number or range is approximate, unless clearly stated otherwise. When any range is described herein, unless clearly stated otherwise, that range includes all values therein and all subranges therein. Any information in any material (e.g., U.S. patent/foreign patent, U.S. patent application, book, article, etc.) that is incorporated by reference herein is incorporated by reference only to the extent that there is no conflict between such information and the other discussion and figures set forth herein. In the event of such conflict, including a conflict that renders any claim herein or claim priority hereto invalid, then any such conflicting information in such material incorporated by reference is specifically not incorporated by reference herein.

Claims

1. A system for delivering insulin to a patient, comprising:

a glucose monitoring device comprising:

at least one input for receiving a blood glucose measurement from the patient;

a processor configured to calculate an amount of insulin to be administered to the patient including an insulin dose based at least in part on a retrospective virtual basal rate determined from a historical record of amounts of insulin delivered to the patient and at least one received blood glucose measurement; and

an insulin delivery device in communication with the glucose monitoring device, the insulin delivery device configured to administer the calculated amount of insulin to the patient;

wherein the retrospective virtual basal rate is derived by matching a plasma insulin concentration pattern inferred from a mathematical model of pharmacokinetic properties of insulin in combination with the historical record of insulin amounts delivered to the patient with a virtual record of basal rate insulin delivery inferred from a mathematical model of pharmacokinetic properties of rapid acting insulin delivered with a continuous infusion pump.

2. The system of claim 1, wherein the at least one input receives a self-glucose monitoring (SMBG) measurement from the patient.

3. The system according to claim 1, wherein the at least one input receives a Continuous Glucose Monitoring (CGM) measurement from the patient.

4. The system of claim 1, wherein the historical record of the amount of insulin delivered to the patient is determined by

Given that σ is at [0, T]In which T is the length of the time period covered by the history.

5. The system of claim 4, wherein said virtual record of basal rate insulin delivery is recorded by

Give, corresponding to the instantaneous plasma insulin concentration

Matching the plasma insulin concentration pattern from historical delivered insulin amounts such that

All tau are at [0, T]Within the range.

6. The system of claim 4, wherein the plasma insulin concentration pattern is defined by

Given that, τ is at [0,T]in the range of I_transient(τ) represents the plasma insulin concentration at time τ in the history; and F_transientIs a function describing the specific instantaneous plasma concentration given (I) the specific PK parameter θ for the insulin type under consideration and (ii) the amount of historically delivered insulin given the initial plasma insulin concentration I (0).

7. The system of claim 6, wherein the processor is further configured to calculate the amount of insulin to be administered to the patient based on a virtual basal rate curve determined from steady state plasma insulin concentrations inferred from a mathematical model of pharmacokinetic properties of insulin in combination with a predetermined insulin delivery schedule, relative to a basal insulin infusion pattern inferred from a mathematical model of pharmacokinetic properties of rapid acting insulin delivered with a continuous infusion pump.

8. The system of claim 7, wherein the initial plasma insulin concentration I (0) is estimated from the steady state plasma insulin concentration.

9. The system of claim 1, further comprising: a subcutaneous continuous glucose monitoring CGM sensor, wherein the glucose monitoring device is in wireless communication with the CGM sensor.

10. The system of claim 1, wherein said insulin delivery device is a portable injection device manually actuated by a user.